This five-year mentored career development award is structured to facilitate my development into an independent, laboratory-based physician scientist in the field of translational thoracic oncology. As an MD-PhD physician scientist, my clinical experiences as a medical oncologist caring for patients with lung cancer inspire the bench science in which I engage. These clinical experiences also provide opportunities to translate scientific discoveries to improve the treatment of patients with lung cancer. My primary mentor is Dr. Charles Sawyers, an international leader in translational oncology. Memorial Sloan-Kettering Cancer Center provides an ideal setting in which to perform patient-oriented, lab-based research. In the laboratory we investigate the mechanism(s) by which some cancer cells acquire dependence upon signaling by an oncoprotein for their survival (oncogene addiction). We have focused on human lung cancers that harbor activating mutations in the epidermal growth factor receptor (EGFR). Human lung adenocarcinomas with activating mutations in EGFR often respond to treatment with EGFR tyrosine kinase inhibitors (TKIs) but the magnitude of tumor regression is variable and transient. We hypothesized that the heterogeneity of treatment response may result from genetic modifiers that regulate the degree to which tumor cells are dependent on the mutant EGFR and, hence, the magnitude and duration of response in patients treated with EGFR TKIs. We used an RNA- interference (RNAi) screening strategy to rationally identify companion therapeutic targets that, when inhibited, might enhance the response of EGFR-mutant lung cancers to the EGFR TKI erlotinib. In initial experiments, we showed that knockdown of CD95/Fas and several components of the NF?B pathway specifically enhanced cell death induced by the EGFR TKI erlotinib in EGFR-mutant lung cancer cells. Activation of NF?B through overexpression of the intermediates c-FLIP or IKK, or silencing of I?B, rescued EGFR-mutant lung cancer cells from EGFR TKI. Genetic or pharmacologic inhibition of NF?B enhanced erlotinib-induced apoptosis in erlotinib-sensitive and erlotinib-resistant EGFR-mutant lung cancer models. Increased expression of the NF?B inhibitor I?B predicted for improved response and survival EGFR-mutant lung cancer patients treated with EGFR TKI. These data identify NF?B as a potential companion drug target, together with EGFR, in EGFR-mutant lung cancers. We propose to further test the hypothesis that the CD95/Fas-NF?B pathway and EGFR are rational companion therapeutic targets in EGFR-mutant lung cancers using state-of- the-art murine models, additional human clinical data, and pathway-selective NF?B pharmacologic inhibitors in the following Specific Aims: 1) Determine if CD95/Fas-NF?B signaling is sufficient to induce EGFR TKI resistance using in vivo models of EGFR- mutant lung cancer, 2) Determine if increased CD95/Fas-NF?B signaling occurs in EGFR-mutant transgenic lung cancer models and patients that are resistant to EGFR TKI, 3) Determine if pathway-selective NF?B inhibitors enhance EGFR TKI responses in EGFR-mutant lung cancer models as a prelude to a clinical trial in appropriately selected patients. More broadly, these studies provide insight into the mechanisms by which tumor cells acquire oncogene dependence and escape from oncogene inhibition.